The immediate-type hypersensitivities, such as extrinsic asthma, hay fever, and allergic responses to certain food or drags, are mediated primarily by immunoglobulin E (IgE). In an IgE-mediated allergic response, the allergen binds to IgE on the surface of mast cells and basophilic leukocytes (basophils). This binding causes a crosslinking of the IgE molecules, and the underlying receptors of the mast cells or basophils for the Fc potion of IgE (Fc.epsilon.R), and triggers the release of pharmacologic mediators such as histamine, the slow-reacting substance of anaphylaxis, and serotonin. The release of these mediators causes the various pathological manifestations of allergy.
Patients affected with allergies or other IgE-mediated hypersensitivities are often treated with histamine antagonists ("anti-histamines") to alleviate symptoms. In addition, during hay fever seasons, desensitization procedures are used to prevent or alleviate allergic reactions. In these procedures, small doses of allergen are injected periodically to induce certain immune responses that may reduce the IgE-mediated responses. Desensitization procedures are more effective in some patients than in others.
It has been suggested that IgE-mediated hypersensitivities might be treated by inhibiting the binding of IgE to mast cells and basophils. For example, synthetic peptides representing various regions of the Fc of IgE (Fc.epsilon.) have been explored as competitive inhibitors for the binding of IgE to the receptors on mast cells and basophils. See e.g., Stanworth, D. R., Molec. Immun. 21:1183-1190 (1984); Stanworth, D. R. and Burt, D. S., Molec. Immun. 23:1231-1235 (1986); Burt, D. S. et al., Molec. Immun. 24:379-389 (1987); Hahn, U.S. Pat. No. 4,683,292: Hamburger, U.S. Pat. Nos. 4,171,299 and 4,161,522. However, presumably due to the fact that the affinity of these peptides for Fc.epsilon.R is lower than for whole IgE, such peptides have not been proved very effective for treatment of allergy.
In recent years, monoclonal antibody methodologies have been employed to map the various antigen and functional epitopes on IgE. Baniyash and Eshhar (Eur. J Immunol. 14:799-807 (1984)) reported that among the several rat monoclonal antibodies made against IgE, three inhibited the binding of mouse IgE to rat basophils cells. Since the antibodies could also induce serotonin release from basophils bound with IgE, the antibodies probably bound sites on Fc which were near but not in the site binding to the receptors for IgE on basophils. More recently the same investigators developed a monoclonal antibody that could inhibit the binding of the IgE to basophils but does not recognize IgE on basophil surface. Baniyash et al., Molec. Immunol. 25:705 (1988). Siraganian et. al. (see Fed. Proc. 40:965 (1981), Fed. Proc. 46:1346 (1987)) reported that among approximately ten mouse monoclonal antibodies made against human IgE, a few did not bind IgE on basophils, and that some of these could inhibit the binding of human IgE to basophils. These studies were directed to the use of monoclonal antibodies to define the various epitopes or functionally related peptidic segments on IgE.
U.S. Pat. No. 4,714,759 describes an immunotoxin specific for the IgE isotype and its use in the treatment of allergy. The immunotoxin comprises an anti-IgE antibody coupled to a toxin. The concept behind the treatment is that the immunotoxin specific for IgE binds to IgE on IgE-producing B cells and kills them. However, the immunotoxin would also bind to IgE on basophils and mast cells, which could lead to anaphylaxis and possibly result in death.